Abstract

Background. Serum markers are used prior to pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies.
Methods. We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a 1st-line (Arm 1) vs. a 2nd-line (Arm 2) screen, in women at high and elevated risk for EOC at five study sites. Semi-annual screening was offered to 208 women aged 25-80 with deleterious BRCA germ-line mutations, and to 834 women aged 35-80 with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women aged 45-80 (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm.
Results. Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in six women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% CI: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1, 11 in Arm 2). Based on 12 women with at least 2 of 3 tests positive (CA125, HE4 or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2.
Conclusions. Positive screens were more frequent when HE4 was included in the primary screen.
Impact. HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen.